A microfluidic toolbox for accelerated development of biocatalytic processes has great potential. This is especially the case for the development of advanced biocatalytic process concepts, where reactors and product separation methods are closely linked together to intensify the process performance, e.g., by the use of in-situ product removal (ISPR). This review provides a general overview of currently available tools in a microfluidic toolbox and how this toolbox can be applied to the development of advanced biocatalytic process concepts. Emphasis is placed on describing the possibilities and advantages of the microfluidic toolbox that are difficult to achieve with conventional batch-processbased technologies. Application of this microfluidic toolbox will potentially make it possible to intensify biocatalytic reactions and thereby facilitate the development towards novel and advanced biocatalytic processes, which in many cases have proven too difficult in conventional batch equipment.
Nucleophilic [18F]-fluorination reactions traditionally include a drying step of the labeling agent in order to achieve a successful substitution. This passage extends the time and complexity required for the whole radiotracer production, with increased hardware and detrimental effects on the radioactive recovery of such a short-lived (t½=109 min) isotope. Because the performance of radiofluorination reactions conducted under microfluidic flow conditions have been demonstrated to be more effective in terms of reaction time and yields, we have tested the tolerance to water present in this specific reaction condition, in view of eliminating the drying step in the process. To this purpose, we tested different substrates selected from typical radiofluorination intermediates. Our results show that water could be tolerated in a microfluidic environment; in particular, we observed a slight decrease in the labeling of aromatic precursors and a significant increase for iodonium salts, whereas the radiochemical yields of the other compounds studied were virtually unchanged. These findings may open the way to the possibility of simpler and faster processes for the production of new 18F-fluorinated positron emission tomography tracers.
Conducting reactions in droplets in microfluidic chips offers several highly attractive characteristics, among others, increased yield and selectivity of chemical syntheses. The use of droplet microfluidic systems in synthetic chemistry is, however, hampered by the intrinsically small throughput of micrometric channels. Here, we verify experimentally the potential to increase throughput via an increase of the scale of the channels.We use the results of these experiments characterizing the processes of (1) generation of droplets, (2) mixing in droplets, (3) inter-phase extraction, and (4) the yield of synthesis of pyrrole, to postulate a number of guidelines for scaling up the throughput of microfluidic droplet systems. In particular, we suggest the rules for maximizing the throughput via an increase of the size of the channels and via parallelization to optimize the throughput of synthesis against the cost of fabrication of the chips and against the kinetic requirements of specific reactions.
Applegate, Jr. R. W., Squier, J., Vestad, T., David, J. O., Marr, W. M., Bado, P., Dugand, M. A., Saidd, A. A. (2006) Microfluidic sorting system based on optical waveguide integration and diode laser bar
A continuous-flow microfluidic electrochemical device (Flux Module) has been designed and evaluated as a practical new laboratory tool to facilitate electrochemical synthetic transformations. Four- and six-electron benzylic oxidations are reported to illustrate the utility afforded by a unique route of synthesis using this technology. Through the utilization of an electron-rich substrate (p-methoxytoluene), a continuous-flow electrochemical oxidation process was optimized. Using a general continuous-flow protocol, a series of diverse tolyl-based substrates were evaluated and the resulting data are reported. The Flux Module results were correlated with the oxidation potential of each substrate as measured by cyclic voltammetry. This established a trend regarding the nature of available oxidation product profiles using this synthesis platform.
The synthesis and functional evaluation of a wide variety of radiolabeled chelator–biomolecule conjugates with high specific activity and radiochemical purity are crucial to development of personalized nuclear medicine. An excellent platform technology for achieving this objective involves use of generator-produced positron emission tomography (PET)-radionuclide 68Ga. Currently, applied manual methodology for optimization and development for new labeling techniques offers only slow screening with relatively high precursor consumption. A capillary-based microfluidic synthesis module with online high-performance liquid chromatography (HPLC) was constructed for the optimization of reaction parameters of 68Ga-PET tracers. This approach enables performance of 68Ga-labeling reactions in 10 μL volumes, followed by sample analysis. The high-throughput capacity of the system allows very rapid optimization. The optimal pH and ligand concentration from the experiments were utilized directly to the production of 68Ga-NODAGA-(RGD)2 and 68Ga-NOPO-RGD. Applying optimal parameters to production of these aforementioned radiopharmaceuticals allowed their synthesis with high radiochemical purity (over 95%) and with surprisingly negligible retention of residual activity in the system.
and economically feasible in biomanufacturing of mAbs.
Continuous-Flow Production of Monoclonal Antibodies in Microfluidics Systems
Culturing adherent mammalian cells in a microfluidic perfusion bioreactor system
A microfluidic technique for combinatorial chemical synthesis of peptidomimetics has been developed. The new method is fast, automated and includes an integrated magnetic separation of inorganic catalysts from reaction products. This proof-of-concept study should lead to methods for generating libraries of compounds suitable for screening for bioactivity.
In an effort to utilize microfluidics to enable photochemistry, we have devised a method for fabrication of devices with UV-transmissive glass. The photochemical device is successfully incorporated into a system utilizing high-pressure capillary mercury lamps and cooling system. We have demonstrated the ability to carry out photochemical transformations with substantial rate acceleration. Furthermore, we highlight the ability to carry out analytical-scale reactions on a pulse flow automated system while modulating wavelength and residence time to identify optimal photochemical reaction conditions. The analytical conditions were also successfully converted to continuous-flow preparative scale.
In recent papers, laboratory microfluidic electrolysis cells with extended channel lengths (0.7–2 m) and narrow interelectrode gap (≤0.5 mm) have been introduced; these cells permit high conversions at a flow rate consistent with the synthesis of products at a rate of multigrams/hour. Such microflow electrolysis cells must be operated with appropriate control parameters if good performance is to be achieved; thus, this paper emphasizes the correct selection of cell current, flow rate, and counter electrode chemistry. It is also shown that, within the limitations, the cells can be used for a number of electrosyntheses in the synthetic laboratory.